Cytotoxic CNS-associated T cells drive axon degeneration during aging.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA577691 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:1. Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon–myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration, but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages—important representatives of the innate immune system—are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging. Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses. Here we examine the role of cytotoxic CD8+ T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases but understudied in the aging CNS. We show that accumulation of CD8+ T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8+ T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify aging-related changes. Mechanistically, we provide evidence that CD8+ T cells drive axon degeneration in a T-cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8+ CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function. 2. Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct mutations in the PLP1 gene result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in these myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates the recruitment of T cells and neural damage, while later targeting of CNS-associated T cell populations is inefficient and has no effect on neurodegeneration. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant oligodendrocyte myelin. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.
2021-02-08 | GSE138891 | GEO
Project description:Axon degeneration and neurological dysfunction in myelin diseases is often attributed to loss of myelin. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. We have previously shown in mice that distinct defects in the proteolipid protein 1 gene result in axonal damage which is largely driven by cytotoxic T cells targeting myelinating oligodendrocytes. Here we show in these mutants that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce aberrant cytoskeletal plasticity within myelinating glial processes and constriction of axons at paranodal domains. Our study identifies detrimental axon-glia interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.
2023-09-29 | GSE224032 | GEO
Project description:Axon degeneration sculpts precise patterns of connectivity in the developing nervous system and is an early pathological hallmark of several adult-onset neurodegenerative disorders. Substantial progress has been made in identifying effector mechanisms that drive axon fragmentation, but far less is known about the upstream signaling pathways that initiate this process. Here we describe a role for the newly discovered axonal Membrane-associated Periodic Skeleton (MPS) –a quasi-1D periodic ultrastructure composed of actin, spectrin and associated molecules– during sensory axon degeneration. We find that trophic deprivation (TD) of sensory axons causes a rapid breakdown in the periodicity of the MPS in distal axons. These structural changes occur prior to and independently of caspase-driven axon fragmentation. We further show that acute actin destabilization to break down the MPS can initiate TD-related retrograde signaling. Actin stabilization prevents MPS breakdown during TD and blocks this signal. Moreover, deletion of βII-spectrin (Sptbn1), an obligate component of the MPS, suppresses this retrograde signaling and protects axons against degeneration. Together our data suggest that ultrastructural plasticity of the MPS underlies the earliest steps of axon degeneration.
2019-03-14 | PXD009854 | Pride
Project description:The adult central nervous system (CNS) has a limited capacity for self-repair. Severed CNS axons typically do not regrow. There is an unmet need for treatments specifically designed to enhance neuronal viability, facilitate CNS axon regeneration, and ultimately restore lost neurological functions to individuals with traumatic CNS injury, multiple sclerosis, and stroke, among other disorders. Here we demonstrate that both mouse and human bone marrow (BM) neutrophils upregulate markers of alternative activation, and acquire the ability to promote neurite outgrowth, following polarization with a combination of recombinant interleukin-4 (IL-4) and granulocyte-colony stimulating factor (G-CSF). Moreover, adoptively transferring IL-4/G-CSF polarized BM neutrophils into experimental models of CNS injury resulted in significant axon regeneration within the optic nerve and spinal cord. The findings reported in this paper hold significant implications for the future development of autologous myeloid cell-based therapies that may bring us closer to effective solutions for reversing CNS damage.
2023-12-01 | GSE244934 | GEO
Project description:Purpose: Injuries to the adult central nervous system (CNS) often result in permanent disabilities because neurons lose the ability to regenerate their axon during development. Although the developmental transition from a growing to a transmitting phase may represent one of the first steps in the gradual loss of axon growth and regeneration ability, the molecular mechanisms regulating this process has yet to be identified. The main goal of this study was to dissect the molecular mechanisms mediating the decline in axon growth ability and its relationship with regeneration failure in the adult CNS. To this end, we sequenced the whole transcriptome of dorsal root ganglia (DRG) neurons in both growth competent and incompetent states at different developmental stages, in diverse culture and in vivo experimental conditions.
2016-09-17 | GSE66128 | GEO
Project description:Drosophila mushroom body (MB) γ neurons undergo axon pruning during metamorphosis through a process of localized degeneration of specific axon branches. Developmental axon degeneration is initiated at the onset of metamorphosis by the pre-pupal rise in the steroid hormone ecdysone. This study identifies genes that alter their expression in MB neurons at the onset and early steps of axon pruning. Keywords: timecourse
2008-06-01 | GSE10012 | GEO
Project description:Transcriptome analysis of neuromuscular junction during degeneration and regeneration of axon terminal
| PRJEB20663 | ENA
Project description:The neuromuscular junction (NMJ) is a specialized tripartite synapse composed of the motor axon terminal, covered by perisynaptic Schwann cells (PSCs), and the muscle fibre, separated by a basal lamina. It is exposed to different kind of injures such as mechanical traumas, pathogens including neurotoxins, and neuromuscular diseases such as amyotrophic lateral sclerosis and immune-mediated disorders, and has retained throughout vertebrate evolution an intrinsic ability for repair and regeneration, at variance from central synapses1. Following peripheral nerve injury, an intense but poorly defined crosstalk takes place at the NMJ among its components, functional to nerve terminal regeneration. To identify crucial factors released by PSCs and the muscle to induce nerve regrowth, we performed a transcriptome analysis of the NMJ at different time points after injection of -latrotoxin, a presynaptic neurotoxin isolated from the venom of the black widow spider. This toxin is a simple and controlled method to induce an acute, localized and reversible nerve terminal degeneration not blurred by inflammation, and can help to identify molecules involved in the intra- and inter-cellular signalling governing NMJ regeneration.
2017-05-30 | E-MTAB-5730 | biostudies-arrayexpress
Project description:Transected axons typically fail to regenerate in the central nervous system, resulting in chronic neurological disability in individuals with traumatic brain or spinal cord injury, multiple sclerosis, and stroke, as well as glaucoma and ischemic reperfusion injury of the eye. Although neuroinflammation is often depicted as detrimental, there is growing evidence that alternatively activated, reparative leukocyte subsets and their products can be deployed to improve neurological outcomes. In the current study we identify a unique granulocyte subset, with characteristics of an immature neutrophil, that has neuroprotective properties and drives CNS axon regeneration in vivo, in part via secretion of a cocktail of growth factors. This pro-regenerative neutrophil promotes repair in the optic nerve and spinal cord, demonstrating its relevance across CNS compartments and neuronal populations. Our findings could ultimately lead to the development of novel immunotherapies that reverse CNS damage and restore lost neurological function across a spectrum of diseases.
2020-09-08 | GSE144637 | GEO
Project description:Drosophila mushroom body (MB) γ neurons undergo axon pruning during metamorphosis through a process of localized degeneration of specific axon branches. Developmental axon degeneration is initiated at the onset of metamorphosis by the pre-pupal rise in the steroid hormone ecdysone. This study identifies genes that alter their expression in MB neurons at the onset and early steps of axon pruning. Experiment Overall Design: y,w animals were staged at -18, 0 and 5 hours relative to puparium formation. RNA was isolated from MB neurons labeled with mCD8::GFP driven by OK107-GAL4 by laser capture microdissection, labeled and hybridized to Affymetrix Drosophila Genome Arrays.
2008-06-18 | E-GEOD-10012 | biostudies-arrayexpress